Paola Turco

Assessment of inhaled BDP-dose dependency of exhaled nitric oxide and local and serum eosinophilic markers in steroids-naive nonatopic asthmatics

The aim of the present study was to assess the dose‐dependency from inhaled steroids of changes of airways inflammation [eosinophils count and eosinophil cationic protein (ECP)] measures in induced sputum and in serum, as well as that of exhaled nitric oxide. Twenty steroid‐naive patients with nonatopic asthma of mild to moderate degree [forced expiratory volume in 1 s (FEV1) = 70% of predicted] and with negative response to the standard tests for allergy were selected; after a 1‐week run‐in period they were randomized to receive a 12‐week treatment period of inhaled beclomethasone dipropionate dry powder given with the Pulvinal® inhaler (Clenil P®, Chiesi Farmaceutici S.p.A., Parma, Italy) in two different dose regimens, 400 μg bid (high dose) or 200 μg bid (low dose), over a double blind, parallel groups design. The following outcome measures were assessed in baseline and after 1, 6 and 12 weeks of treatment: FEV1 (l), eosinophils count in sputum (%), is ECP (μg/l), serum eosinophils count (%), serum ECP (μg/l) and exhaled NO (ppb). The results showed that all the considered parameters improved in both groups: the increase over baseline of FEV1 and the decrease of NO were significant at any time in the high‐dose group and only at week 12 in the low‐dose group (NS between groups), whereas the markers of eosinophilic activity showed more consistent reductions in the high‐dose than in the low‐dose group when measured in induced sputum (P < 0.05 between groups after 6 and 12 weeks for eosinophils count and after 12 weeks for ECP). Decreases over baseline of markers measured in serum were more rapid in the high‐dose group, without differences between groups. A marked trend towards a negative correlation was found between FEV1 and ECP, (r = −0.72, P < 0.05), between FEV1 and eosinophils in sputum (r = −0.31, NS) and between FEV1 and exhaled NO (r = −0.38, NS), all of them only in the high‐dose group. The results of the study demonstrate that changes of levels of eosinophilic activity in the airways are dependent from the daily dose of inhaled steroids when measured in induced sputum and that the local assessment can therefore represent a practical and noninvasive method to monitor the extent of airways inflammation.

Famotidine and theophylline pharmacokinetics. An unexpected cimetidine-like interaction in patients with chronic obstructive pulmonary disease.

SummaryThe results of research studies conducted to date in vitro and in healthy volunteers are practically all concordant in demonstrating the lack of any kind of interference between famotidine and microsomal oxidative metabolism.The pharmacokinetics (elimination half-life, area under the plasma concentration-time curve, clearance and volume of distribution) of theophylline 3.4 mg/kg as an intravenous infusion over 5 min (a dosage previously used to test drug interactions with cimetidine and ranitidine) were evaluated in 7 patients with chronic obstructive pulmonary disease (COPD) and peptic ulcer disease before and after 8 days’ treatment with famotidine 40mg at night. The results indicate that famotidine can induce substantial and statistically significant slowing of theophylline elimination with a cimetidine-like interaction profile.

Sensitivity of the COPD assessment test (CAT questionnaire) investigated in a population of 681 consecutive patients referring to a lung clinic: the first Italian specific study

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality at global level even if still underestimated. The insufficient use of specific tools for an objective definition and staging, the inadequate awareness of COPD, but also a difficult patient-to-doctor communication, can contribute to the poor management of COPD. A very simple, short and sensitive questionnaire (the “COPD Assessment Test” - CAT questionnaire) is now available for assessing the impact of COPD on the patient’s health. The present study was designed to provide such evidence using data generated throughout Italy.MethodsThe Italian validated version of the CAT questionnaire was distributed to 681 consecutive COPD patients of different severity (males = 480), well matched for age, gender, smoking habit, geographical distribution, BMI, dyspnoea score and educational level. The CAT score variability was investigated vs all anagraphic, and clinical variables, and spirometric indices of lung function (regression). No Italian data are available to our knowledge on the CAT use, neither in General Medicine, nor in the specialist setting.ResultsData of this study confirmed that the CAT questionnaire is a sensitive, simple, and quick tool for assessing the respiratory status of COPD patients. The CAT score proved not conditioned by the patient’s age, gender, body size, geographical origin, and educational level. It was inversely correlated with the spirometric values, even if not uniquely linked to them.ConclusionsThe CAT score does not represent a surrogate measurement of lung function: it is an instrument which focuses on different areas of respiratory health in COPD patients, thus providing an useful and objective tool for the long-term clinical and therapeutic monitoring of COPD patients in the specialist outpatient setting.

Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: Results of a double blind, placebo-controlled trial

BACKGROUND Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased airway and systemic inflammation. There is evidence that erdosteine accelerates recovery from AECOPD by reducing airway inflammation. AIM To investigate the dose-dependent antioxidant/anti-inflammatory activity of erdosteine in COPD patients. METHODS In this single-centre, double blind, double dummy study, patients with mild-to-moderate COPD (GOLD stage II-III), were randomised to receive either placebo or two dosages of oral erdosteine (300 mg tid or 300 mg bid + 1 capsule of indistinguishable placebo) for 28 days in addition to their standard treatment. Primary variables were plasma reactive oxygen species (ROS) and 8-isoprostane levels, while secondary variable was lung function (FEV1; FEV1/FVC; FEV1 short-term reversibility), all assessed in baseline; every two weeks during the study, and one week after the end of the study. RESULTS Baseline demographic characteristics, plasma ROS and 8-isoprostane levels and lung function were not significantly different in the 24 eligible patients (14 males, aged 38-75 years). At 2 weeks, there was a dose-dependent decrease in ROS in the erdosteine groups. By week 4 there were significant differences in ROS levels compared to baseline between patients receiving 900 mg/day (p < 0.003) and those receiving 600 mg/day (p < 0.04). This effect continued in the follow-up week (p < 0.021). Erdosteine also lowered 8-isoprostane plasma levels after 4 weeks (p < 0.01), and this effect lasted over the post-treatment week. Moreover, % FEV1 reversibility after salbutamol 400 mcg obtained after a 4 -week treatment of erdosteine 900 mg/day was significantly higher than that obtained after 600 mg/day (p < 0.01). Erdosteine was well tolerated and no treatment-related adverse event was reported. CONCLUSIONS Results confirm the antioxidant dose- and time-dependent activity of erdosteine, and support the utility of including erdosteine it in the therapeutic strategy for the prevention and treatment of oxidative stress-induced inflammation, which frequently leads to AECOPD occurrence.

Cognitive dysfunction in severe chronic obstructive pulmonary disease (COPD) with or without Long-Term Oxygen Therapy (LTOT)

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition which can lead to comorbidities of variable severity, cognitive dysfunction included. The role of supplemental oxygen in preventing COPD-induced cognitive deterioration is still debated, but only episodically investigated. The aim of this study was to compare the cognitive pattern of hypoxemic COPD subjects treated with long-term oxygen (LTOT) to that of patients of comparable severity assuming oxygen on irregular basis, and to normal reference values.MethodsLung function, arterial blood gases, health status, and cognitive function measured by means of four psychometric tests focusing different domains of cognition (such as: MMSE, Clock test; TMT-A; TMT-B) were assessed in 146 well matched hypoxemic COPD patients (males n = 96, 66%; mean age = 70.5 ± 12.9). Seventy-three patients were assuming long-term oxygen (LTOT), while the remaining seventy-three were only using oxygen as needed (AN). Regarding statistics, t test and ANOVA (Duncan test) were used to analyze data, assuming a p < 0.05 as the lowest limit of significance.ResultsEven though all COPD patients showed a poorer psychometric profile vs corresponding normal reference values, LTOT patients showed a lower prevalence of severe deterioration in cognition. Also the extent of impairment was significantly lower in these patients when assessed by TMT-A and TMT-B (p < 0.012 and 0.001, respectively), but not when measured by MMSE and Clock test (both p = ns). Several domains of cognition are variably affected by persistent hypoxemia in COPD patients. A panel of psychometric tools is needed for identifying the pattern of cognitive dysfunctions in these patients. Memory and attention (functions assessed by MMSE and Clock test) are only mildly-moderately affected, while visual processing, reproduction of numeric sequences, cognition flexibility, and shifting capacity (functions assessed by TMT-A and TMT-B) are much more deteriorated (p < 0.012 and p < 0.001, respectively).ConclusionsOnly LTOT allows to preserve significantly (p < 0.022) cognitive functions from the COPD-induced deterioration. This assumption is of strategic value for COPD patients who are prescribed long-term oxygen because they frequently are not aware of the cognitive risks related to their condition.

Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment

BackgroundInformation on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.MethodsA cohort of 132 severe COPD patients (94 males; 71.4 years ± 8.8 sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13 g/dL; group B: ≥13 < 15 g/dL; group C: ≥ 5 < 16 g/dL; group D: ≥16 g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3 years.ResultsLTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1 mmHg ± 6.6sd to 65.1 mmHg ± 8.7 sd, p < 0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p < 0.001). PaCO2 dropped within the first year of LTOT (from 49.4 mmHg ± 9.1sd to 45.9 mmHg ±7.5 sd, p < 0.001): the t0-t1 comparison proved significant (p < 0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p < 0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb > 15 g/dl (ANOVA p < 0.001); anemic subjects (Hb < 13 g/dl) ameliorated not significantly in the same period (ANOVA = 0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.ConclusionsLTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.

Clinical and pharmacoeconomic profile of COPD patients with FEV1 50--60% predicted: pilot study on the impact of the extended indication of ICS/LABA.

Background: The use of inhaled corticosteroids (ICS) and long-acting β2 adrenergics (LABA) in fixed combination (ICS/LABA) was recently extended to COPD patients with a baseline FEV1 50—60% predicted, thus broadening the original guideline indications (GOLD 2006) that limited their use only to stages III and IV. Method: The present study was carried out to assess the clinical profile of this new subset of patients, with a view to providing data for future studies on the impact of this novel extension of ICS/LABA use in COPD. Results: Data from the present observational cross-sectional study suggest that COPD patients with FEV1 50—60% predicted depict a dichotomic condition: actually, even though resembling milder patients in terms of frequency and severity of their respiratory symptoms, they are much more similar to severer patients in terms of rate of hospital admissions and resource consumption (p50.01). In other words, this subset of patients seems to represent a peculiar condition in the evolutional phase of COPD during which therapeutic treatment should be intensified in order to slow down the disease progression effectively. Nevertheless, independently of the severity, the general therapeutic approach to COPD was found to be greatly inadequate when compared to GOLD guidelines, particularly in terms of appropriateness. Conclusions: These findings should pave the way for future studies aimed to long-term monitoring of main outcomes and to evaluate the overall impact of earlier ICS/LABA use on disease progression and lung function decline in COPD.

Changes of clinical outcomes and health care resources in moderate and in severe COPD treated uniquely with tiotropium 18 mcg od for twenty-four months.

UNLABELLED Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease characterized by incompletely reversible bronchial obstruction. The effects of current therapeutic options in early stages of COPD have been poorly investigated in the past, being this specific topic revamped by the results of recent secondary analyses from large international trials. AIM To measure and monitor in real life the changes in main clinical outcomes and health care resources in patients suffering from mild-to-moderate and severe COPD treated with only tiotropium br. for twenty-four months. METHODS The population sample of the present observational retrospective study consists of 319 COPD subjects (214 males; average age 71.7 years ± 06 se) automatically extracted from the DataBase of the Health Care Institution. Inclusion criteria were: age ≥ 40 y; basal FEV1 < 80% predicted and FEV1/FVC < 70%; regular treatment with only 18 mcg tiotropium br. for the following two years. All subjects were divided into two subsets according to their FEV1 basal value: (Group A ≤ 50%, and Group B >50% predicted). Lung function; n. exacerbations; n. hospitalizations; absenteeism; n. GPs visits, and use of systemic steroids or antibiotics were checked during the observational period and mean values compared in both subsets with those of the twelve months preceding tiotropium br. (such as during other therapeutic strategies). T test was used for checking the comparability of groups, while ANOVA--Duncan test was used to compare the trends of all variables over time; p < 0.05 was accepted. RESULTS Group A, 154 individuals (104 males; mean age 72.1 years ± 0.51 se) had a mean FEV1 value of 45.4% pred. ± 0.61 se, while the remaining 165, Group B (111 males; mean age 71.4 years ± 0.60 se) had a mean FEV1 value of 65.5% pred. ± 5.7 se (p < 0,01). The two subsets were well matched for gender, age, and previous use of systemic steroids, but significantly different in terms of basal lung function, COPD morbidity, and antibiotic use. Basically, the impact of COPD confirmed higher in severe patients even if it was unexpectedly remarkable in mild-to-moderate individuals in terms of consumption of health care resources. The overall reduction in COPD morbidity was significant in both groups, but the improvement in FEV1 and in other main long-term outcomes observed in subjects with mild-to-moderate COPD was particularly significant and substantial (p < 0.001), these subjects confirming to be worth of earlier therapeutic attention. CONCLUSIONS 18 mcg tiotropium br. monotherapy for twenty-four months on a regular daily basis enables a significant minimization of COPD impact, and consents the progressive lung function recovery also in mild-to-moderate individuals, thus suggesting a possible role of tiotropium br. in affecting the natural history of COPD.

Telemedicine and LTOT in Italy: a 20-Year Experience

aging and monitoring ever-growing numbers of patients distributed over large territories stimulated specialists who were involved in long-term oxygen treatment (LTOT) programs to radically change their approach to the chronic management of patients with severe respiratory disease needing continuous oxygen at home. Although it is praiseworthy, the model for intervention used and consolidated in Italy (i.e., a model based for several years on small numbers of health professionals – doctors and nurses – and on groups of volunteers periodically aiding patients at home in their daily activities) frequently proved to be inadequate in ensuring the strict monitoring that is needed for the great majority of these patients. Moreover, although irreplaceable, the involvement of local volunteers (and of new organizations) who frequently took on institutional roles led paradoxically to the partial unawareness of health institutions of the real burden of LTOT, which was generally neglected or underestimated in their public health planning documents. From a general point of view, economic resources for public health progressively decreased in those years (such as at the end of the 1980s), while the regulatory approach to LTOT remained lax or nonexistent throughout Italy. Depending on both the local sensitivity to the problem and the personal engagement of doctors and nurses, the net result was the spontaneous development of a large number of uncontrolled and heterogeneous protocols for managing LTOT around Italy. The total economic impact and the true cost-effectiveness of these local protocols were unknown and were not assessed at that time. In order to minimize or reduce the effects of these variables, our group moved toward innovative technologies that were aimed at daily telemetric contacts with patients at home and their interactive remote monitoring. We were (and still are) convinced that telemedicine should provide, even though remote, the advantages of a specialist organization, of equipment, and of a particular know-how that can be available at the patient’s home when needed. The project started with the triennial support (1990-1992) of the Department for Public Health of the Regione Veneto (project no. 324/03/90), who strongly supported this pioneer research (Fig. 1) with the aim of providing patients and their families with new health and therapeutic options able to encourage de-hospitalization while greatly improving quality of life at home. The project was also carried out with the support of the National Research Council (CNR, document no. 6345/91) and of VitalAire Italia, who agreed to carry out technological research Telemedicine and LTOT in Italy: a 20-Year Experience

Transcutaneous O2 and CO2 Monitoring of Bronchial Responsiveness in FEV1 Non-Responder Asthmatics during Ketotifen and Placebo Treatment

Effects of ultrasonically nebulized distilled water (UNDW) on PtcO2 and PtcCO2 time courses were studied in 26 mild asthmatics (FEV1 non-responders) in basal conditions and monitored after 2, 6, 12 and 18 weeks of randomly allocated treatment with ketotifen 1 mg b.i.d. or placebo. Magnitude and duration of both PtcO2 and PtcCO2 changes due to UNDW inhalation were progressively normalized only by ketotifen. Partial but significant protection against UNDW-induced hyperventilation was achieved after 2 weeks of treatment, complete protection (also against UNDW-induced hypoxia) being achieved later. In view of the CO2 dependency of respiratory drive and the primary structural targets of the hypo-osmotic bronchial challenge employed, these results suggest that ketotifen may affect the mucosal structures of the bronchial airways, thereby acting as a mucosal protective drug.